Field of the Invention
This invention relates generally to formulations and methods for treatment, delay, and/or prevention of disease. More in particular, the present invention comprises multi-component formulations and methods for the treatment, delay, and/or prevention of cognitive decline, including Alzheimer's disease, and/or other neurodegenerative diseases.
Description of Related Art
Alzheimer's Disease (“AD”) is believed to be a multifactorial degenerative disease rather than the result of a single malfunction or agent. Although AD is usually accompanied by the abnormal accumulation of extracellular deposits or plaques of β-amyloid protein (AB) and intracellular neurofibrillary tangles of tau protein (NFTs), extensive research has not isolated or identified a cause for the accumulation, nor shown that β-amyloid protein or NFTs are the cause rather than effect of AD. In fact, approximately 30 percent of AD patients have no AB plaques or NFTs at death, and approximately 30 percent of cognitively normal adults do have AB plaques and NFTs at death. AB plaques may even be protective against harmful soluble AB oligomers. (Exhibit 1). Instead, clinical and epidemiological studies have identified numerous contributing factors to AD (Exhibit 2).
Many of the pathologic characteristics of AD, inflammation, oxidative stress, impaired cerebral blood flow and glucose utilization, result from body imbalances, including stress, obesity, and an overloaded immune system (Exhibit 4). In addition, AD has a lengthy, non-linear, accelerating, and degenerative prodromal time period with ample opportunity for preventive intervention, and about 95 percent of AD cases are sporadic late-onset.
PHA-57 is a patented drug which combines dimethyl sulfoxide (DMSO) and fructose 1,6-disphosphate (FDP) (Exhibit 8). DMSO and FDP are small and naturally occurring molecules. PHA-57 can be introduced into the body orally or by injection. DMSO, by itself and in combination with FDP, has many desirable effects (Exhibit 9). It is a powerful antioxidant (Exhibit 10). It supplies energy in the form of ATP. It increases cerebral blood flow without altering blood pressure when significant cell damage is present. It inhibits neuronal cell death after central nervous system injury. It protects against blood clotting (Exhibit 11). It counters calcium dysregulation (Exhibit 54). It is a chemical chaperone which has reduced protein misfolding in prion diseases (Exhibit 12, Exhibit 18). PHA-57 has reversed memory dysfunction in rats. It has shown safety and efficacy in a clinical trial with humans for stroke. DMSO alone has demonstrated efficacy with rats as a neuroprotectant for stroke (Exhibit 13).
Cerebrolysin is a proprietary drug which is a mixture of brain peptides, i.e., proteins and amino acids. It is derived from pigs, which have genetic and other similarities to humans (Exhibit 14). Cerebrolysin is not patented and has been in worldwide use for over 25 years. It is approved for use for AD in more than 30 countries, although not the United States. Cerebrolysin is both neurotrophic and neuroprotective. It is administered by injection, although a weaker derivative of it has been administered orally in pill form and is sold as a dietary supplement in the United States. Cerebrolysin has been shown in numerous trials over time to be both safe and effective (Exhibit 15).
The composition known as the Brain Energizer (Changlong Bio-pharmacy, China; distributed by Glory Medicine and Healthcare Co. Ltd., Hong Kong), is similar to cerebrolysin in that it is made from processed porcine brain peptides. The Brain Energizer is different than cerebrolysin in that it is in powder/pill form, is taken orally, and includes several herbal ingredients. The Brain Energizer demonstrated efficacy without safety problems in a Chinese clinical trial with humans for dementia (Exhibit 16).
There is no clinical evidence as to how cerebrolysin or the Brain Energizer work. PHA-57, cerebrolysin, and the Brain Energizer have all proven to have minimal side effects. The disadvantage of cerebrolysin and the Brain Energizer is that they are both animal (porcine) products, which are susceptible to spreading disease, both in reality and perception.
An equally efficacious and potentially superior alternative is an artificially designed natural neuroprotective protein (Exhibit 17). The most promising alternative by far is the exogenous stimulation of endogenous neuroprotective proteins, including but not limited to nicotinamide mononucleotide adenylyl transferase (“NMNAT”), heat shock proteins, synucleins, crystallins, and other neuronal molecular chaperones. These proteins repair protein misfolding, counter tauopathy, boost immunity, exert neuroprotective effects in dendrites and axons, and are positively associated with recovery brain plasticity in honeybees. (Exhibit 18, Exhibit 12, Exhibit 19, Exhibit 30, Exhibit 57, Exhibit 73).
Furthermore, there are numerous herbals which exhibit various effects. Some herbals are known to strengthen the immune system, increase circulation, provide antioxidant and anti-inflammatory effects, and directly affect and protect neurons before, during, and after stress and injury. Some herbal ingredients are known as herbal enhancers, that is, they improve the efficacy of other herbals when administered in combination. Herbals can be used individually, in combination, or by extracting the active ingredient. Herbals have been tested in the laboratory and clinically in animals and humans. However, clinical and scientific trials with herbals are relatively new, and herbal use is primarily traditional. The widespread traditional use of herbals does indicate safety.
Herbals are the ideal complementary component. Historically, herbals have been used in combination, are not overwhelmingly potent, and are time-tested. Herbals are natural transporters which can help with drug delivery. Herbals are known to be used with the Brain Energizer.
A primary issue with regard to administration of herbals is which herbal or herbals to use. Curcumin has shown extensive anti-inflammatory and neuroprotective properties, and the ability to regulate insulin and glucose uptake (Exhibit 19). Ginkgo biloba and its extracts have shown promise (Exhibit 20). Other herbs have produced positive results (Exhibit 21).
Current research on several herbal extracts, focusing on the traditional Chinese medicine, Lycium barbarum and its fruit, wolfberry, has shown extensive and varied neuroprotective effects (Exhibit 22, Exhibit 18).
Foods are only a step away from herbals. Proper diet, including calorie restriction and weight loss (Exhibit 23), is an element both of overall health and AD prevention (Exhibit 24). However, for certain nutrients there is a more direct link.
Blueberries contain numerous anthocyanins, including callistephin and kuroman, which preserve mitochondrial structure. Blueberries have demonstrated antioxidant and anti-inflammatory effects which retard brain aging in rats and improve memory in older adults (Exhibit 25).
Cinnamon contains a variety of polyphenols which reduce free radicals, preserve mitochondrial membranes, halt glutamate decline, and modulate immune response and inflammation. Cinnamon has also improved metabolic syndrome and insulin metabolism, and insulin dysfunction has been linked to AD (Exhibit 26).
Acai has exhibited powerful antioxidant capacity (Exhibit 27). Pomegranate juice has shown the ability to protect and enhance the activity of nitric oxide, in addition to neuroprotective effects in both adult and neonatal mice brains (Exhibit 28).
Alpha lipoic acid, by itself and in combination with melatonin and trans-resveratrol, has shown antioxidant and anti-inflammatory effects which slowed the progression of early stage AD, and in combination with exercise, has improved spatial learning and memory in mice (Exhibit 29, Exhibit 3). Resveratrol, which is found in red grapes and wine, has increased cerebral blood flow in healthy adults, evidenced strong antioxidant, anti-inflammatory, and neuroprotective activity and β-amyloid degradation, shown anti-obesity and anti-aging effects in various organisms other than humans, and together with catechin demonstrated synergistic protective action against β-amyloid. Resveratrol has also shown the ability to stimulate neuroprotective proteins and epigenetic effects (Exhibit 30, Exhibit 18, Exhibit 73).
Oxyresveratrol, which is found in mulberry and has one more hydroxyl group than resveratrol, is a stronger antioxidant than resveratrol, with superior neuroprotection and lower toxicity in patient's with AD, stroke, and Parkinson's disease (Exhibit 31).
Moderate consumption of alcohol or wine may slow the rate of progression from mild cognitive impairment to AD in older adults (Exhibit 32).
Folic acid, which stimulates production of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has decreased homocysteine and improved cognitive function in older adults (Exhibit 33, Exhibit 38).
Apple juice concentrate has produced neuroprotective effects in mice through antioxidant and other mechanisms (Exhibit 34). Peach extract has inhibited acetylcholinesterase in rats (Exhibit 35). Walnut extract, which combines DHA and polyphenols, has shown anti-inflammatory properties, improved cognitive function in aged rats, and inhibited AB fibrillization (Exhibit 36).
Caffeine has reversed cognitive impairment and β-amyloid protein levels in mice (Exhibit 37). Essential fatty acid supplementation, especially omega-3 DHA and including krill oil and plant-derived perilla oil, has shown promise for insulin regulation, improved brain health and cognition in non-demented adults, and AD prevention, along with anti-inflammatory and antioxidant effects.
The human brain is 50 percent to 60 percent lipids, primarily DHA. DHA predominates in the metabolically active gray matter and is an essential element of neuronal membranes and neurotransmission, but decreases with age because of oxidation. Fish oil, including EPA, is an anticoagulant which may increase blood flow and the supply of nutrients to the brain and assist in removing toxic metabolites and proteins which accompany neurodegeneration (Exhibit 38, Exhibit 19).
Quercetin, a flavonoid in fruits and vegetables, has both decreased oxidative stress and inhibited acetylcholinesterase in cells (Exhibit 39).
Grape juice and grape extracts have promoted nitric oxide bioavailability and reduced β-amyloid in human and porcine cells, and have shown antioxidant and anti-inflammatory properties in mice (Exhibit 40).
Epigallocatechin-3-gallate, a component of green tea, has displayed antioxidant neuroprotective effects in rat neurons (Exhibit 41).
Watermelon juice, a source of citrulline, has increased arginine in humans and increased arginine with improved vascular function in diabetic rats (Exhibit 42, Exhibit 47, Exhibit 48).
Vitamins A, C, and E have shown potential to reduce oxidative stress and protect against AD (Exhibit 43). Vitamin D has promoted immune system clearance of AB and has decreased inflammation and aging in human cells, and Vitamin D deficiency has been associated with cognitive decline in elderly adults (Exhibit 44).
Coenzyme Q10 has decreased oxidative stress and NFTs, and restored molecular signaling in mice (Exhibit 45). Multinutrient and multiherbal combinations have shown neuroprotective effects (Exhibit 46).
Vascular nitric oxide, along with its precursors, L-arginine and L-citrulline, is a recognized aid to cerebral blood flow. It has antioxidant, anti-inflammatory, and neuroprotective effects, and it is increased by a high nitrate diet (Exhibit 47). Extensive experiments with nitric oxide have been conducted (Exhibit 48).
Melatonin has demonstrated antioxidant and neuroprotective effects in AD (Exhibit 49).
Colla corii asini, a donkey skin extract from China, often mixed with herbs, has shown the ability to improve microcirculation (Exhibit 50).
Aspirin and Vitamin C in combination have evidenced neuroprotective effects. Aspirin alone, in addition to its multiple health benefits, may also have a possible link from plants to the human immune system and neuroprotection (Exhibit 51).
Allopregnanolone, a metabolite of progesterone, has promoted neurogenesis and cognitive enhancement in mice (Exhibit 52).
Eklonia Cava, an extract of brown algae, has shown antioxidant and anti-inflammatory neuroprotective effects, and has improved memory and inhibited acetylcholinesterase and β-amyloid protein in rodents (Exhibit 53).
Combating calcium dysregulation and excess, a degenerative process leading to plaques both in AD and heart disease, has shown promise (Exhibit 54).
Zinc supplementation has increased neuroprotective protein levels in healthy old adults (Exhibit 55, Exhibit 18).
A variety of techniques have also shown promise for AD, including intranasal delivery, nanotechnology (Exhibit 62), homeopathy, neurohormesis, ayurveda, omental transposition, moxibustion, odor administration, hyperbaric oxygen therapy, music, photobiomodulation, computerized cognition training, and human photosynthesis (Exhibit 56). Environmental enrichment has countered the effects of stress on the cognitive ability of mice, provided cognitive benefits to aged mice without impacting β-amyloid, and has been positively associated with recovery brain plasticity and endogenous neuroprotective proteins in honeybees (Exhibit 57).
The FDA has made new rules for botanicals and has recently approved its first botanical drug (Exhibit 58). The standards for approval are no different than for conventional drugs, but these rules take into consideration the different qualities of herbals. Combining herbals with a conventional drug, which is more familiar, should make the approval process easier. Herbals can be “fingerprinted” and verified in order to assure consistency and overcome the objection that herbals cannot be standardized (Exhibit 59).
On Dec. 15, 2010 the FDA issued a draft guidance entitled “Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination”. The draft states, in part, that “[r]ecent scientific advances have increased our understanding of the pathophysiological processes that underlie many complex diseases, such as cancer, cardiovascular disease, and infectious diseases. This increased understanding has provided further impetus for new therapeutic approaches that rely primarily or exclusively on combinations of drugs directed at multiple therapeutic targets to improve treatment response and minimize development of resistance” (Exhibit 60).